Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors.
A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K(i)=0.1 nM, EC(50)=4.5 nM) and selective (CC(50) (Huh-7 cells)>50 microM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration.
Vendeville
Sandrine
S
Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium.
Nilsson
Magnus
M
de Kock
Herman
H
Lin
Tse-I
TI
Antonov
Dmitry
D
Classon
Björn
B
Ayesa
Susana
S
Ivanov
Vladimir
V
Johansson
Per-Ola
PO
Kahnberg
Pia
P
Eneroth
Anders
A
Wikstrom
Kristina
K
Vrang
Lotta
L
Edlund
Michael
M
Lindström
Stefan
S
Van de Vreken
Wim
W
McGowan
David
D
Tahri
Abdellah
A
Hu
Lili
L
Lenz
Oliver
O
Delouvroy
Frederic
F
Van Dooren
Marleen
M
Kindermans
Natalie
N
Surleraux
Dominique
D
Wigerinck
Piet
P
Rosenquist
Asa
A
Samuelsson
Bertil
B
Simmen
Kenneth
K
Raboisson
Pierre
P
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002219:Carbamates; D011392:Proline; D015842:Serine Proteinase Inhibitors; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus